It is estimated that approximately 330,000 individuals suffer an episode of sudden cardiac arrest every year in the United States. Yet, the percentage of individuals who are successfully resuscitated and leave the hospital alive with intact neurological function averages only 7% nationwide. Efforts to successfully restore life are formidably challenging. They require not only that cardiac activity be initially reestablished but that injury to vital organs be prevented or minimized. A closer examination of resuscitation statistics reveals that efficient emergency medical services (EMS) systems can initially restore cardiac activity in 30 to 40% of sudden cardiac arrest victims. Yet, nearly 40% die before admission to a hospital presumably from recurrent cardiac arrest or complications during transport. Of those admitted to a hospital, 60% die before discharge as a result of myocardial dysfunction, hypoxic brain damage, systemic inflammatory responses, intercurrent illnesses, or a combination thereof. Driving poor outcome is the severe injury that tissues suffer consequent to ischemia and reperfusion.
A cardiac arrest is the cessation of normal circulation of the blood due to failure of the ventricles of the heart to contract effectively resulting in the cessation of blood delivery to the whole body. As a consequence cells of the whole body suffer injury that result from oxygen starvation. Lack of oxygen supply to the brain causes victims to immediately lose consciousness and stop breathing. Cardiac arrest is different from a heart attack (myocardial infarction). In a cardiac arrest the heart suddenly stops beating. In a heart attack, blood flow to a region of the heart muscle is disrupted. That region of the heart muscle deprived of blood flow suffers injury which might lead to cell death if blood flow is not restored promptly. During a heart attack, only a part of the heart ceases to work properly; the rest of the heart muscle continues to work promoting blood flow albeit the total work produced by the heart may be sometimes diminished. However, heart attacks can sometimes lead to cardiac arrest in which the heart as whole stops beating and ceases to promote blood flow into the systemic circulation (as described above).
In apparently healthy adults, cardiac arrest is often precipitated by ventricular fibrillation. Ventricular fibrillation most often is associated with underlying coronary artery disease. In this setting, ventricular fibrillation may be the initial manifestation of a heart attack. However, ventricular fibrillation does not have to be associated with a heart attack, but can be associated with electrical abnormalities of the heart muscle originating in a region of the heart in which there is reduction of blood flow or disproportionate increase in oxygen demands in such region. Ventricular fibrillation can also be associated with the following: structural abnormalities of the heart—such as those caused by ischemic heart disease or by non-ischemic cardiomyopathies—that alters the normal propagation of electrical impulses creating areas in which chaotic electrical activity can originate and propagate through the rest of the heart muscle; associated with trauma to the heart; congenital or acquired abnormalities of ion channels that regulate the way in which the electrical impulse of the heart is initiated and propagated; the administration of drugs that can alter such ion channels; abnormalities in the chemical composition of the blood that can alter the way in which the electrical impulse of the heart is initiated and propagated; and abnormalities in the valves of the heart. Cardiac arrest can also occur without ventricular fibrillation, for example in cases in which the heart stops beating because of asystole in which there is no electrical impulses originating from the heart, or because of pulseless electrical activity in which electrical impulses originating from the heart are not effective to promote normal contraction of the heart muscle. Cardiac arrest caused by asystole or pulseless electrical activity is typically associated with conditions leading to severe curtailment of the amount of oxygen delivered to the heart muscle, which may be associated with respiratory failure or severe loss of circulating blood volume. Cardiac arrest caused by asystole or pulseless electrical activity can also be associated with existing cardiac disease, especially when severe heart failure has developed. However, asystole or pulseless electrical activity more commonly occurs after a period of untreated or ineffectively treated ventricular fibrillation. In this setting, the ventricular fibrillation activity gradually decreases and eventually ceases leading to asystole or pulseless electrical activity. This explains why individuals in whom cardiac arrest is precipitated by ventricular fibrillation, at the time of initial rhythm analysis asystole or pulseless electrical activity is present in more that 50% of the instances.
In children, cardiac arrest is more commonly caused by severe curtailment of oxygen delivery to the heart muscle, which may be associated with near-drowning or respiratory failure. However, children can also suffer cardiac arrest caused by ventricular fibrillation.
After onset of cardiac arrest, profound global myocardial ischemia develops. The ensuing resuscitation efforts promote flow through the ischemic myocardium, which—albeit obligatory for resuscitation—creates conditions for reperfusion injury. As a consequence several functional myocardial abnormalities develop during cardiac arrest and the resuscitation effort that in of itself can compromise the capability for reestablishing cardiac activity. These abnormalities include the progressive loss of left ventricular myocardial distensibility during cardiac resuscitation that manifests by left ventricular wall thickening with reductions in cavity size and which limits the ability of chest compression to promote forward blood flow. Early after return of spontaneous cardiac activity, there is prominent ventricular ectopic activity with frequent episodes of refibrillation. In addition, systolic and diastolic left ventricular function is reversibly impaired causing variable degrees of hemodynamic dysfunction. We have previously shown that these myocardial abnormalities can be ameliorated by inhibition of the sodium-hydrogen exchanger isoform-1 (NHE-1) using cariporide (Ayoub I M, Kolarova J D, Yi Z, Trevedi A, Deshmukh H, Lubell D L, Franz M R, Maldonado F A, Gazmuri R J. Sodium-hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability. Circulation 2003; 107:1804-1809; Gazmuri R J, Ayoub I M, Hoffner E, Kolarova J D. Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation 2001; 104:234-239; Gazmuri R J, Hoffner E, Kalcheim J, Ho H, Patel M, Ayoub I M, Epstein M, Kingston S, Han Y. Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med 2001; 137:43-55; Kolarova J D, Ayoub I M, Gazmuri R J. Kolarova J D, Ayoub I M, Gazmuri R J. Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship. Am J Physiol Heart Circ Physiol 2005; 288:H2904-H2911; Kolarova J, Yi Z, Ayoub I M, Gazmuri R J. Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation. Chest 2005; 127:1327-1334).
The present invention discloses that administration of the glycoprotein hormone EPO also serves to attenuate these myocardial abnormalities and favor improved resuscitation. EPO is a 30.4-kDa glycoprotein best known for its action on erythroid progenitor cells and regulation of circulating red cell mass. However, EPO also activates potent cell protective mechanisms during ischemia and reperfusion in a broad array of tissues, including the myocardium (Cai Z, Manalo D J, Wei G, Rodriguez E R, Fox-Talbot K, Lu H, Zweier J L, Semenza G E Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 2003; 108:79-85; Calvillo L, Latini R, Kajstura J, Len A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA 2003; 100:4802-4806; Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta E G, Talan M I. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA 2003; 100:11612-11617; Parsa C J, Matsumoto A, Kim J, Riel R U, Pascal L S, Walton G B, Thompson R B, Petrofski J A, Annex B H, Stamler J S, Koch W J. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 2003; 112:999-1007; Tramontano A F, Muniyappa R, Black A D, Blendea M C, Cohen I, Deng L, Sowers J R, Cutaia M V, El Sherif N. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 2003; 308:990-994; Cai Z, Semenza G L. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation 2004; 109:2050-2053; Lipsic E, van der M P, Henning R H, Suurmeijer A J, Boddeus K M, van Veldhuisen D J, van Gilst W H, Schoemaker R G. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol 2004; 44:473-479; Parsa C J, Kim J, Riel R U, Pascal L S, Thompson R B, Petrofski J A, Matsumoto A, Stamler J S, Koch W J. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem 2004; 279:20655-20662; Wright G L, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy M O. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J 2004; 18:1031-1033; Namiuchi S, Kagaya Y, Ohta J, Shiba N, Sugi M, Oikawa M, Kunii H, Yamao H, Komatsu N, Yui M, Tada H, Sakuma M, Watanabe J, Ichihara T, Shirato K. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol 2005; 45:1406-1412). These protective effects are mediated through genomic and non-genomic mechanisms; with the non-genomic mechanisms being particular relevant to acute protection (Bullard A J, Govewalla P, Yellon D M. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 2005; 100:397-403; Rafiee P, Shi Y, Su J, Pritchard K A, Jr., Tweddell J S, Baker J E. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol 2005; 100:187-197; Nishihara M, Miura T, Miki T, Sakamoto J, Tanno M, Kobayashi H, Ikeda Y, Ohori K, Takahashi A, Shimamoto K. Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3 beta. Am J Physiol Heart Circ Physiol 2006; 291:H748-H755).
EPO has been traditionally viewed as a primary regulator of red blood cell production (Graber S E, Krantz S B. EPO and the control of red cell production. Annu Rev Med 1978; 29:51-66). Yet, recent studies demonstrate the EPO also exerts protective effects on the myocardium in the setting of ischemia and reperfusion injury (Cai Z, Manalo D J, Wei G, Rodriguez E R, Fox-Talbot K, Lu H, Zweier J L, Semenza G L. Hearts from rodents exposed to intermittent hypoxia or EPO are protected against ischemia-reperfusion injury (Circulation 2003; 108:79-85; Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M. Recombinant human EPO protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA 2003; 100:4802-4806; Tramontano A F, Muniyappa R, Black A D, Blendea M C, Cohen I, Deng L, Sowers J R, Cutaia M V, El Sherif N. EPO protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 2003; 308:990-994; Cai Z, Semenza G L. Phosphatidylinositol-3-kinase signaling is required for EPO-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation 2004; 109:2050-2053; Lipsic E, van der Meer P, Henning R H, Suurmeijer A J H, Boddeus K M, van Veldhuisen D J, van Gilst W H, Schoemaker R G. Timing of EPO treatment for cardioprotection in ischemia/reperfusion; United States Patent Application Pub. No. 2004/0009908A1; United States Patent Application Pub. No. 2004/0198663A1; United States Patent Application Pub. No. 2005/0075287; International Patent Application WO 03/057242; International Patent Application No. WO 2004/00464). In a rat model of myocardial infarction caused by left anterior descending coronary artery (LAD) occlusion and reperfusion, administration of recombinant human erythropoietin (rhEPO) attenuated post infarct deterioration in hemodynamic function by reduction of cardiomyocyte loss, attenuated the reactive hypertrophy of surviving cardiomyocytes, and also prevented apoptosis (Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta E G, Talan M I. EPO reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA 2003; 100:11612-11617).
These and other aspects and attributes of the present invention will be discussed with reference to the following drawings and accompanying specification.